Respiratory diseases such as asthma and other chronic obstructive pulmonary diseases (COPD) are characterized by the constriction or narrowing of the airways of the lungs. Asthma is a chronic disease in which sufferers have repeated attacks of difficulty in breathing and coughing. The prevalence and severity of asthma, as well as its associated mortality, have increased in the last few decades. In the United States, 40 million people have asthma and they account for 3 million emergency department visits, 500,000 hospitalizations, and nearly 6,000 deaths annually [see Rodrigo, G., Rodrigo, C. and Hall, J. (2004) Acute asthma in adults: a review. Chest 125: 1081-1102].
The majority of asthmatics (90-95%) suffer from the mild to moderate form of the disease and can control the disease with appropriate treatment. However, the 5-10% of asthmatics that suffer from the severe form of the disease, also known as severe persistent or acute severe asthma, are faced with frequent and life-threatening attacks. During an acute asthma attack, the airways (e.g., bronchi and bronchioles) are greatly narrowed by swelling (caused by inflammation of the inner lining of the bronchi/bronchioles), bronchoconstriction (caused by contraction of the bronchi/bronchioles smooth muscles) and mucus plugging (caused by the excess production of mucus produced by mucous gland secretions and cells lining the airway wall). The resultant narrowed airways make it more difficult for air to pass through to adequately ventilate the air sacs in the lungs, resulting in reduction of oxygen (hypoxaemia) in the blood and reduced oxygen supply to vital organs.
An important first step for treatment during an acute asthma attack is to reduce swelling, relax the muscles of the airways and loosen mucous plugs, thus opening the airways and making it easier to breathe. In addition, once the airways have been opened, administration of conventional therapeutics such as beta-2-agonists, anticholinergics and anti-inflammatory agents such as glucocorticosteroids will be more efficient as these drugs will be able to reach their active site more effectively.
COPD is a slowly progressive disease of the airways that is characterized by the gradual loss of lung function. Patients with COPD often require emergency treatment and sometimes hospitalizations during periods of exacerbations of their disease. COPD leads to chronic airflow obstruction, which is defined as a persistent decrease in the rate of airflow through the lungs when the person breathes out (exhales). Symptoms such as wheezing and shortness of breath are relieved when airflow obstruction decreases by reversing bronchial smooth muscle spasm, inflammation, and increased secretions.
Cystic fibrosis is an example of an obstructive lung disorder that results in bronchiectasis and progressive declines in FEV1. In this disease, there is a genetic defect in the transport of chloride or chlorine across the airway lining (epithelial) cells. This results in a reduced water content in the mucous blanket with increased viscosity of the mucus. The abnormal mucus becomes infected, which results in destruction and fibrosis of the bronchial wall. The mucous plugs and inflammation cause airway obstruction. Even with optimal treatment, most affected individuals die in their third or fourth decades.
The present invention is useful, for example, during acute asthma attacks as it provides potent and rapid bronchial relaxation so that both air and, if necessary, medication can be more effectively delivered to the lungs. Further, the present invention is useful for treating any respiratory disease where the airways are narrowed due to inflammation of the airways or constricted due to airway smooth muscle contractions (bronchoconstriction) and have mucous plugs such as are found in asthma, COPD and other obstructive lung diseases, such as bronchiectasis.